Colombo, Dario (2010)
Ph.D. thesis, University of Birmingham.
Tetraspanins are a superfamily of four-transmembrane proteins. They associate laterally with one another and with other transmembrane proteins to form membrane microdomains, in which associated proteins are regulated. Tetraspanins regulate diverse processes such as cell signalling and fusion, intracellular trafficking, viral infection and cancer. The primary aim of this thesis was to study a previously uncharacterized tetraspanin, Tspan18. Unlike other tetraspanins, over-expression of Tspan18 in lymphocyte cell lines activated an NFAT/AP-1 reporter, which responds to calcium and MAPK signalling. In DT40 B cell lines, Tspan18 signalling was independent of Lyn, Syk, PLC2 and IP3 receptors, which are essential for B cell receptor signalling. However, Tspan18 signalling did require extracellular calcium and the calcium-activated phosphatase calcineurin, which activates NFAT. Additional studies that included the Jurkat T cell line showed that Tspan18 could not activate the MAPK-responsive AP-1 promoter, but instead mimicked the effect of the calcium ionophore ionomycin. For the secondary thesis aim, over-expression of Tspan18 or other tetraspanins did not affect signalling by the platelet collagen receptor GPVI. Finally, Tspan18 mRNA was found to be relatively highly expressed in endothelial cells and peripheral blood leukocytes. Together these data suggest a role for Tspan18 in calcium signalling on these cell types.
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